Approximately 100 million people worldwide suffer from type II diabetes [non-insulin dependent diabetes mellitus (NIDDM)], which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes of which are as yet not clearly understood. Hyperglycemia is considered to be the major risk factor for the development of diabetic complications, and is likely to contribute directly to the impairment of insulin secretion seen in advanced NIDDM. Normalization of plasma glucose in NIDDM patients would be predicted to improve insulin action, and to offset the development of diabetic complications. An inhibitor of the sodium-dependent glucose transporter (SGLT2) in the kidney would be expected to aid in the normalization of plasma glucose levels, and perhaps body weight, by enhancing glucose excretion.
Hyperglycemia is a hallmark of type II diabetes; consistent control of plasma glucose levels in diabetes can offset the development of diabetic complications and beta cell failure seen in advanced disease. Plasma glucose is normally filtered in the kidney in the glomerulus and actively reabsorbed in the proximal tubule. SGLT2 appears to be the major transporter responsible for the reuptake of glucose at this site. The SGLT specific inhibitor phlorizin or closely related analogs inhibit this reuptake process in diabetic rodents and dogs resulting in normalization of plasma glucose levels by promoting glucose excretion without hypoglycemic side effects. Long term (6 month) treatment of Zucker diabetic rats with an SGLT2 inhibitor has been reported to improve insulin response to glycemia, improve insulin sensitivity, and delay the onset of nephropathy and neuropathy in these animals, with no detectable pathology in the kidney and no electrolyte imbalance in plasma. Selective inhibition of SGLT2 in diabetic patients would be expected to normalize plasma glucose by enhancing the excretion of glucose in the urine, thereby improving insulin sensitivity, and delaying the development of diabetic complications.
Ninety percent of glucose reuptake in the kidney occurs in the epithelial cells of the early S1 segment of the renal cortical proximal tubule, and SGLT2 is likely to be the major transporter responsible for this reuptake. SGLT2 is a 672 amino acid protein containing 14 membrane-spanning segments that is predominantly expressed in the early S1 segment of the renal proximal tubules. The substrate specificity, sodium dependence and localization of SGLT2 are consistent with the properties of the high capacity, low affinity, sodium dependent glucose transporter previously characterized in human cortical kidney proximal tubules. In addition, hybrid depletion studies implicate SGLT2 as the predominant Na+/glucose cotransporter in the S1 segment of the proximal tubule, since virtually all Na-dependent glucose transport activity encoded in mRNA from rat kidney cortex is inhibited by an antisense oligonucleotide specific to rat SGLT2.
SGLT2 is a candidate gene for some forms of familial glucosuria, a genetic abnormality in which renal glucose reabsorption is impaired to varying degrees. None of these syndromes investigated to date map to the SGLT2 locus on chromosome 16. However, studies involving highly homologous rodent SGLTs strongly implicate SGLT2 as the major renal sodium-dependent transporter of glucose and suggest that the glucosuria locus that has been mapped encodes an SGLT2 regulator. Inhibition of SGLT2 would be predicted to reduce plasma glucose levels via enhanced glucose excretion in diabetic patients.
C-aryl glucosides, a class of SGLT2 inhibitors, have been observed to act as orally active antidiabetic agents. In particular, these C-aryl glucoside SGLT2 inhibitors have been found to be useful for treating or delaying the progression or onset of diabetes, especially type I and type II diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels. The conditions, diseases, and maladies collectively referred to as “Syndrome X” (also known as Metabolic Syndrome) are detailed in Johannsson, J. Clin. Endrocrinol. Metab., 82:727-34 (1997).
Such C-aryl glucoside SGLT2 inhibitors may be used alone or to complement existing therapy treatments, including sulfonylureas, thiazolidinediones, metformin, and insulin, and to avoid the potential side effects typically associated with the use of these other agents. Further details about the C-aryl glucosides and derivatives thereof, may be found in PCT World Application WO 01/27128 A1, U.S. Pat. No. 6,414,126, U.S. patent application Ser. No. 10/151,436, and U.S. patent application Ser. No. 10/117,914, the entire disclosures of which are incorporated herein by reference.
A method of producing C-aryl glucoside SGLT2 inhibitors which provides a telescoped or one-pot operation, or optionally a multi-vessel reaction, and which minimizes the production of intermediates during production of the final product for improved yield and purity would be desirable. It would further be useful for such a method to be stereoselective in operation, to allow for the production of a substantially enantiomerically pure product. Such a method could be applied to the preparation of compounds including but not limited to 1-C-(4′-ethyldiphenylmethane-3-yl)-β-D-glucopyranose, 1-C-(6-methyl-4′-(methylthio)diphenylmethane-3-yl)-β-D-glucopyranose, 1-C-(6-chloro-4′-ethoxydiphenylmethane-3-yl)-β-D-glucopyranose. Also desirable is a method of forming crystalline complexes of the compounds synthesized.